This proposal is focused on the physiological functions of Protein Kinase A (PKA) in the regulation of adiposity, feeding, and energy expenditure. The holoenzymeform of PKA interacts with cAMP to release active catalytic subunits that phosphorylate a variety of intracellular targets. This process is modulated by scaffolding proteins (AKAPs) and the expression of various isoforms of PKA with different biochemical properties. The goal of my laboratory is to develop mouse genetic approaches that can be used to study the role of PKA in physiological pathways that are not easily manipulated in cell culture models. Targeted disruption of the Rllp regulatory subunit gene of PKA creates mice that are lean and resistant to obesity and display a two-fold increase in nocturnal activity. These phenotypes have recently been traced to the brain and we propose to focus our efforts on determining the brain regions and specific cell types that are responsible. We also propose experiments to determine the changes in kinase activity that account for these phenotypes and the potential substrates that are involved. The application of mouse genetics to the study of body weight regulation has identified novel hormones, neural pathways, and intracellular signaling systems that have all proven to be applicable to humans. Our goal is to further understand the signaling interactions in the hope that this will lead to future therapeutic treatments for obesity.